Dr. Thon

CEO/CSO, Platelet BioGenesis

Projects

We are making functional platelets for human infusion. Platelets are essential for hemostasis, and platelet transfusions are widely used to treat patients with inherited or acquired thrombocytopenia. Consequently, the limited availability of donor platelets owing to their 5-day shelf life, immunogenicity of platelet products, and risk of sepsis due to bacterial contamination are of serious clinical concern. New strategies for generating platelets in vitro from non-donor dependent sources are necessary to obviate these risks and meet transfusion needs. My Research Goals are to develop a bio-mimetic system to study the cell biological and molecular pathways involved in platelet production, and produce useable numbers of clinically viable human platelets for infusion.

We are accomplishing this by generating a microfluidics platform that recapitulates the human bone marrow cellular environment and vasculature under physiologically relevant shear forces. Our biochips fully integrate megakaryocyte and platelet biology with extracellular matrix composition and stiffness, hemodynamics and microvascular geometry to study the physiological determinants of platelet formation. Functional equivalence is determined by comparing culture-derived platelets to blood platelet controls.

BACKGROUND

Platelet production represents the final stage of megakaryocyte development. Bone marrow megakaryocytes mature adjacent sinusoidal blood vessels, and rely on cell-cell, cell-matrix, and soluble factor interactions to regulate their development. Mature megakaryocytes extend long, branching cellular structures, designated proplatelets, which function as the assembly lines for platelets. Proplatelets are comprised of platelet-sized swellings in tandem arrays that are connected by thin cytoplasmic bridges, and extend into the sinusoidal blood vessels of the bone marrow. Extracellular matrix proteins are a major constituent of the bone marrow vascular niche, and have been shown to promote proplatelet formation in vitro.

GAPS IN OUR UNDERSTANDING AND TRANSLATION INTO MEDICINE

While thrombocytopenia is a major clinical problem encountered across a number of diseases and treatments, the mechanisms underlying physiological platelet production are not well understood. An essential gap in this understanding is how the bone marrow microenvironment impacts platelet generation. Novel approaches to reverse-engineer key components of the bone marrow vascular niche provide insight into these functions, and will be instrumental to understand and control the transition of megakaryocytes into platelets for medical use. Our goal is to mimic bone marrow physiology and use biologically-inspired engineering to advance culture-derived human platelets to the clinic.

SIGNIFICANCE

Platelets play a critical role in stimulating clot formation and vascular injury repair, for which more than 2.17 million apheresis-equivalent platelet units are transfused yearly in the United States. Morbidity and mortality from bleeding due to low platelet count is a major clinical problem encountered across multiple conditions including chemotherapy, radiation treatment, trauma, immune thrombocytopenic purpura, organ transplant surgery, severe burns, sepsis, and genetic disorders. Nevertheless, platelet production remains poorly understood, and as a result platelet units are still derived entirely from human donors, despite serious clinical concerns relating to their inherent immunogenicity and associated risk of sepsis. Increasing demand for platelet transfusions, compounded by a near-static pool of donors, and a 5-day platelet unit shelf-life resulting from bacterial testing and storage-related platelet deterioration, have resulted in clinically significant platelet shortages. Modeling the human bone marrow vascular microenvironment will yield new mechanistic insights into physiological platelet production and establish a biomimetic drug development platform to increase platelet count in vivo (autotransfusion), thereby circumventing transfusion-related complications. Production of an alternative source of human platelets in vitro will obviate risks associated with platelet procurement and storage, and help meet growing transfusion needs.

 Manuscripts

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